The purpose of this proposal is to provide career development and mentored research experience in sickle cell disease (SCD) for the Principal Investigator. He will gain sophisticated analytic skills through completion of his PhD in clinical investigation and practical experience through coordination of a multidisciplinary clinical research project. This training and the rich research environment of Johns Hopkins University will help assure his development into an independent investigator with expertise in SCD and the use of imaging and neuropsychological testing in clinical research. The long-term goal of the project is to prevent the central nervous system (CMS) complications of SCD (stroke, silent cerebral infarct (SCI), and neurocognitive impairment). By age 18, nearly 10% of patients with SCD will have a stroke and another 15 - 20% will have SCI. Most (79%) of these children, and 36% with a normal MRI of the brain, will have cognitive impairment. Measurement of the velocity of blood flow in the major cerebral arteries by transcranial Doppler can identify children at risk for stroke, but there are no established tests to identify children at risk of SCI or cognitive impairment. Cerebral blood flow (CBF) as measured by nuclear medicine studies or MRI is often elevated in SCD and may identify children with early, potentially reversible, cognitive impairment and those at risk for SCI. We will test the hypothesis that CBF is related to neurocognitive function in children with SCD. This will be accomplished through attainment of the following specific aims: 1) to evaluate the relationship between baseline CBF and neurocognitive function. We will measure blood flow to cerebral gray matter by continuous arterial spin-labeled (CASL) MRI and neurocognitive function by a global test of intelligence in a cross-sectional study of 113 children with SCD and 35 normal sibling controls. 2) To evaluate the relationship between regional CBF and specific domains of neurocognitive function. We will measure regional CBF in the distribution of the right and left anterior, middle, and posterior cerebral arteries and corresponding specific functional domains (attention and executive function, language, fine motor, and visual perceptual) by focused neuropsychological testing. 3) To evaluate the longitudinal effect of CBF on neurocognitive function. We will repeat the MRI studies and neuropsychological testing after three years in a cohort study of children with SCD and their sibling controls. The early identification of children at risk for CMS complications of SCD is essential to target the use of existing therapies and permit the efficient evaluation of new therapies. CBF measurements may provide information needed to reduce SCI, cognitive impairment, and the resulting academic failure that limits the potential of many children with SCD.